The current preferred treatment for Type II, non-insulin dependent diabetes as well as obesity is diet and exercise, with a view toward weight reduction and improved insulin sensitivity. Patient compliance, however, is usually poor. There are no currently approved medications that adequately treat either Type II diabetes or obesity. The invention described herein is directed toward an effective and timely treatment for these serious diseases.
One therapeutic opportunity that has been recently recognized involves the relationship between adrenergic receptor stimulation, anti-hyperglycemic effects, and metabolic events such as increased basil metabolic rate. Compounds that act as β3 adrenergic receptor agonists have been shown to exhibit a marked effect on lipolysis, thermogenesis, and serum glucose levels in animal models of Type II (non-insulin dependent) diabetes.
The β3 receptor, which is found in several types of human tissue including human fat tissue, has roughly 50% homology to the β1 and β2 receptor subtypes yet is considerably less abundant. The importance of the β3 receptor is a relatively recent discovery since the amino-acid sequence of the human receptor was only elucidated in the late 1980's. A large number of publications have appeared in recent years reporting success in discovery of agents that stimulate the β3 receptor. Despite these recent developments there remains a need to develop a selective β3 receptor agonist which has minimal agonist activity against the β1 and β2 receptors.
The present invention provides methods of treating Type II diabetes, treating obesity, and stimulating the β3 receptor. In addition, the present invention also provides novel compounds that are selective β3 receptor agonists and as such are useful for treating Type II diabetes, obesity, and stimulating the β3 receptor. U.S. Pat. No. 4,503,067 discloses carbazolyl-(4)-oxypropanolamine compounds, some of which are within the scope of formula I, as β-adrenoceptor antagonists and vasodilators.